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Innovative approaches to antipsychotic drug pharmacology

Project descripton

Schizophrenia is a severe and complex disease, the etiology of which remains unknown. One of the main sources of information about the disease and its pharmacology is the study of the mechanisms of action of currently available antipsychotics, such as the “gold-standard” clozapine. It is widely accepted that the interactions of antipsychotic drugs with multiple neurotransmitter receptors (particularly G protein coupled receptors, GPCRs) reflect their actions in the treatment of multiple symptoms linked with disruptions of neurotransmitter systems. At the cellular level, recent studies have described new relevant mechanisms of signaling mediated by GPCRs, as receptor dimerization, functional selectivity of psychoactive drugs and their distinct transcriptomic fingerprints when they act at the same receptor. So far, antipsychotic pharmacology studies have considered the complexity of the involved phenomena only to a limited extent.

For these reasons, the general aim of this project is to study the global patterns of cell signaling involved in the effect of antipsychotic drugs, in order (i) to discover novel pharmacological targets for antipsychotic therapy and (ii) to obtain new hits that could be used as proof of concept for innovative antipsychotic drug discovery.

The project will be carried out by a multidisciplinary team with experience in public/private early drug discovery, distributed in four subprojects. Highly informative series of novel compounds will be obtained by two chemistry subprojects (medicinal chemistry and chemical biology). These, together with other compounds currently available, will be assayed using transcriptomic and pharmacological methods in the pharmacology subproject, and the resulting data will be analyzed using molecular modeling and multivariate methods by the computational subproject. We expect to obtain new mechanistic insights and promising targets, which will be validated and exploited by designing new drug-like compounds.

The present project has been founded by the spanish Ministerio de Ciencia e Innovación (Investigación Fundamental no-orientada subprogram), SAF2009-13609-C04